4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as Selective Cyclooxygenase-2 Inhibitors:  Enhancement of the Selectivity by Introduction of a Fluorine Atom and Identification of a Potent, Highly Selective, and Orally Active COX-2 Inhibitor JTE-522

• Published in: Journal of medicinal chemistry Vol. 45; no. 7; pp. 1511 - 1517
• Main Authors: Hashimoto, Hiromasa, Imamura, Katsuaki, Haruta, Jun-ichi, Wakitani, Korekiyo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.03.2002; Amer Chemical Soc
• Subjects: Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Arthritis, Rheumatoid - drug therapy; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Fluorine - chemistry; Humans; Inhibitory Concentration 50; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Isoenzymes - metabolism; Life Sciences & Biomedicine; Medical sciences; Membrane Proteins; Models, Chemical; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - chemistry; Prostaglandin-Endoperoxide Synthases - metabolism; Science & Technology; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Temperature; H SYNTHASE-2 INHIBITOR; RATS; ROFECOXIB; PROFILE; PROSTAGLANDIN SYNTHASE; MESSENGER-RNA; Prostaglandin-endoperoxide synthase; Cyclohexane derivatives; Isozyme; Toxicity; Diseases of the osteoarticular system; Inflammatory joint disease; Arthritis; Selectivity; Gastroduodenal; Structure activity relation; Ulcer; Adjuvant; Chemical synthesis; Oxazole derivatives; Oxygen nitrogen heterocycle; Human; Immunopathology; Sulfonamide; Enzyme; Benzene derivatives; Oral administration; Enzyme inhibitor; Inflammation; In vitro; Non steroidal antiinflammatory agent; In vivo; Chemotherapy; Experimental disease; Treatment; Fluorine Organic compounds; Oxidoreductases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010484p

A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.